A common antiretroviral medication improves cognitive ability in a mouse model of Down's syndrome
Lamivudine, a commonly used antiretroviral medication for the treatment of HIV, improves the cognitive capacity of a mouse model of Down's syndrome, according to a new joint study by researchers at the Centre for Genomic Regulation (CRG) and the IrsiCaixa AIDS Research Institute, a centre jointly promoted by the "la Caixa" Foundation and the Catalan Government's Department of Health. The article has been published in the Journal of Cellular and Molecular Medicine.
Although clinical studies are needed to confirm that the drug has a similar effect in humans, the results of this animal study highlight the potential of using pharmacological interventions such as lamivudine - or other drugs capable of blocking the same therapeutic target - as a treatment to improve cognitive impairment in people with Down's syndrome.
Down syndrome is a condition caused by the presence of an extra chromosome in the genome. Normally, the human genome contains 23 pairs of chromosomes, but in the case of Down's syndrome, one of these pairs has three copies instead of two, namely chromosome number 21. This results in an intellectual disability that can range from mild to moderate, affecting general cognitive skills such as memory, attention span and speech. In addition, when they reach adulthood, people with Down's syndrome experience accelerated ageing. This results in the onset of cognitive decline that, in the general population, would be typical of older people.
People with Down's syndrome are also at increased risk of Alzheimer's disease because their chromosome 21, which is triplicated, contains the genes for a protein that is particularly relevant to Alzheimer's disease. This protein, known as amyloid precursor protein (APP), has the ability to accumulate in the brain generating protein aggregates that cause altered brain function. The presentation of these protein aggregates is common in most adult individuals over the age of 40 with Down syndrome.
To support independent living, most people with Down syndrome undergo psychosocial interventions such as cognitive stimulation therapy, one of the only treatment options currently available as there are currently no pharmacological interventions. Now, the results of this study point to a possible drug treatment pathway and position retrotransposons as a potential therapeutic target of great interest for Down syndrome.
Retrotransposons are segments of DNA that change their location within the genome; to do this, they create RNA copies of themselves to move out of the area of the genome where they are located and then convert back into DNA so that they can be inserted back into the genome, but in a different location. These segments can insert themselves into specific areas of the genome and, by chance, position themselves in gene promoter regions associated with neurodegenerative diseases, boosting their activity. The activity of these DNA segments to jump from one site to another in the genome increases with age.
In addition, retrotransposons have some similarities to HIV in that, like HIV, they need to switch from DNA to RNA, and vice versa, to make copies of themselves. Thus, researchers hypothesised that the use of molecules capable of inhibiting HIV replication - such as the enzyme reverse transcriptase - could also work to block retrotransposons.
"Both HIV and retrotransposons need the same molecule to make copies of themselves: the enzyme reverse transcriptase," explains Dr Bonaventura Clotet, director of IrsiCaixa. "The scientific community had shown that lamivudine, an inhibitor of this enzyme already used against HIV, decreased the activation of retrotransposons in aged mice. We therefore thought that the use of lamivudine could also be useful in counteracting the cognitive impairment associated with Down's syndrome," he adds.
To demonstrate this, researchers worked with Ts65Dn mice, the most studied animal model of Down's syndrome to date. For four months, one group of mice was treated with lamivudine, while the other was used as a water-only control. The team then conducted several behavioural experiments designed to test locomotor activity, recognition memory and anxiety. They found that the mice receiving lamivudine showed improved cognitive abilities. The results of the study hypothesise that the observed benefits of lamivudine may be due to its effect on one or more variants of the APP gene.
"Our work aims to support people with Down syndrome and their families by giving them more options for independent living, particularly for individuals affected by early-stage Alzheimer's disease," says Dr Mara Dierssen, CRG researcher and co-author of the study.
"We still need drug treatments that consistently help to improve memory, attention and language functions, or prevent cognitive decline associated with ageing. This study is a step towards changing this situation, as it reveals that retrotransposon activity is an interesting mechanism to study not only in ageing, but also in neurodevelopmental disorders," concludes Dr Dierssen.
Lamivudine is a prescription drug approved by US and EU medical authorities for the treatment of HIV infection in adults and children. The next step for the research team is to start clinical trials with the drug for people with Down's syndrome and Alzheimer's disease.
